The present invention relates to hypoglycemic agents which are certain 4-[2-(5-aryl- and heteroaryloxazolidin-2-on-3-yl)alkyl]benzoic acids and ester, glycinamide, oxazole and thiazolidinedione derivatives thereof.
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g., chloropropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g., phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily, usually self, injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, as reviewed by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].
Subsequently, Schnur, U.S. Pat. Nos. 4,332,952, 4,342,771, 4,367,234 and 4,617,312 disclosed various classes of 5-aryl- and 5-heteroaryl-substituted oxazolidine- and thiazolidine-2,4-diones; Kawamatsu et al., U.S. Pat. No. 4,461,902 described certain p-substituted-5-benzylthiazolidine-2,4-diones; and Holland, U.S. Pat. No. 4,430,337 described certain 5-alicyclic-substituted oxazolidine-2,4-diones; all as having hypoglycemic activity. More recently, Eggler et al. disclosed hypoglycemic thiazolidine-2,4-diones of the type ##STR1## wherein the dotted line represents an optional double bond, n=0, 1 or 2; X is O, S, SO, SO.sub.2, CH.sub.2, CO, CHOH or NR.sup.x ; R.sup.x is an acyl group; R.sup.y is H, CH.sub.3 or C.sub.2 H.sub.5 ; variously and optionally substituted at the 2,3-positions of the X-containing heterocyclic ring.
A variety of compounds generally encompassed by the formula ##STR2## have also been recently disclosed as hypoglycemic and antiobesity agents, summarized as follows: Smith et al. U.S. Pat. No. 4,309,443 (including R.sup.j =H, F, Cl, CF.sub.3 ; R.sup.k =H, F, Cl; R.sup.p =OH; R.sup.q =H; R.sup.s =H, CH.sub.3 ; m=1-5; R.sup.t =CH.dbd.CH--COOH): Ainsworth et al. (I), U.S. Pat. No. 4,338,333 (including R.sup.j, R.sup.k, R.sup.p, R.sup.q and R.sup.s the same as Smith et al.; m=1-6; R.sup.t =O-Z.sup.a --CO.sub.2 H; Z.sup.a =alkylene, alkenylene or alkynylene of up to 10 carbons); Mills et al., U.S. Pat. No. 4,391,826 (including R.sup.j =H or o-F; R.sup.k =H; R.sup.p =OH; R.sup.q =H; R.sup.s =H, CH.sub.3 or C.sub.2 H.sub.5 ; m=2; R.sup.t =OH, alkanoyloxy, CONH.sub.2, CONHCH.sub.3, COOCH.sub.3 or COOC.sub.2 H.sub.5); Ainsworth et al. (II), U.S. Pat. No. 4,478,849 (including R.sup.j, R.sup.k, R.sup.p, R.sup.q, R.sup.s and m the same as Ainsworth et al. (I); R.sup.t is COOH or a salt, ester or amide thereof); Hindley, U.S. Pat. No. 4,593,023 (including R.sup.j =H, halogen, CF.sub.3 ; R.sup.k =H or halogen; R.sup.p and R.sup.q are taken together with the carbon and nitrogen to which they are attached to form a 2-oxomorpholine ring; R.sup.s =H or CH.sub.3 ; m=1 or 2 and R.sup.t =--O(CH.sub.2).sub.a CO.sub.2 H or --COOH, or an ester thereof, where a=1-6); Cantello, U.S. Pat. No. 4,607,033 (including R.sup.j, R.sup.k, R.sup.s, R.sup.t, and m the same as Hindley, but R.sup.p and R.sup.q taken together with the carbon and nitrogen to which they are attached to form a morpholine or homomorpholine ring; Ainsworth et al. (III), U.S. Pat. No. 4,596,800 (R.sup.j, R.sup.k, R.sup.p, R.sup.t, and m the same as Hindley, but R.sup.p and R.sup.q are taken together with the carbon and nitrogen to which they are attached to form a 2-hydroxymorpholine ring); Ainsworth et al. (IV), European Patent Application No. 40,915 (including R.sup.j =m--CH.sub.3 ; R.sup.k =H; R.sup.p =OH; R.sup.q =H; m=1-3; R.sup.t =--COOH); Borge et al., European Patent Application No. 142,102 (including R.sup.j =H, halogen or CF.sub.3 ; R.sup.k =H or halogen; R.sup.p =OH; R.sup.q =alkyl; m=1 or 2; R.sup.t =--O(CH.sub.2).sub.a CO.sub.2 H or --COOH, or an ester thereof).